Wk 10: Schizophrenia

  1. Define schizophrenia
    • Schizophrenia is a disorder characterised by faulty perception and beliefs; a change in levels of motivation and emotional expressiveness; disordered thinking and behaviour; and changes in cognition.
    • Common for people with the disorder to withdraw from other people and from everyday reality, often into a life of odd beliefs (delusions) and hallucinations.
  2. Schizophrenia statistics
    • The symptoms of schizophrenia invade every aspect of a person’s life: the way someone thinks, feels and behaves.
    • Not surprisingly then, these symptoms can interfere with maintaining stable employment, living independently and having close relationships with other people.
    • 21.5 percent being employed over a 12-month period and 85 percent being dependent upon government welfare payments for their livelihood.
    • only 17.1 percent of people with a psychotic illness, the most severe of which is schizophrenia, were living with a partner.
    • nearly 38 percent had experienced stigma or persecution from other people in the past year.
    • Substance use rates are high with 63.2 percent of males and 41.7 percent of females having a lifetime history of abusing or being dependent upon cannabis or other illicit drugs. A similar proportion abused alcohol.
    • This level of abuse may reflect an attempt to achieve some relief from the symptoms, however, it does also contribute to the risk of relapse as well as the level of disability.
    • About 5 percent of people with schizophrenia will end their own life by suicide, usually in the first few years of having the illness.
    • In Australia, people with a psychotic illness have very high rates of diabetes mellitus type 2, hypertension and metabolic syndrome, which, when combined with their high rates of smoking and unhealthy lifestyle, greatly increase the risk of premature death.
    • The lifetime morbid risk of developing schizophrenia is around 7 in 1000, and it is no more common in men than women.
    • Schizophrenia sometimes begins in childhood, but it usually appears in late adolescence or early adulthood and usually presents somewhat earlier in men than in women. 
    • People with schizophrenia typically have a number of acute episodes of their symptoms early in the course of their illness and less severe but still debilitating symptoms between episodes.
  3. Schizophrenia DSM-5
    • DSM-5 criteria for schizophrenia
    • Two or more of the following symptoms for at least one month; one symptom should be either 1, 2 or 3:
    • 1. delusions
    • 2. hallucinations
    • 3. disorganised speech
    • 4. disorganised (or catatonic) behaviour
    • 5. negative symptoms (diminished motivation or emotional expression).
    • Functioning in work, relationships or self-care has declined since onset.
    • Signs of disorder for at least six months; or, if during a prodromal or residual phase, negative symptoms or two or more of symptoms 1–4 in less severe form.
  4. Clinical description of schizophrenia
    • People with the disorder typically have only some of these symptoms at any given time.
    • It is possible to diagnose two different people with schizophrenia with virtually no symptom overlap.
    • Schizophrenia symptoms can be grouped in a number of ways, but are perhaps best described in five broad domains; positive, negative, disorganised, cognitive and mood/anxiety.
  5. Summary of the 5 major symptom domains in schizophrenia
    • Positive symptoms: Delusions, hallucinations
    • Negative symptoms: avolition, alogia, anhedonia, blunted affect, asociality
    • Disorganised symptoms: Disorganised behaviour, disorganised speech
    • Cognitive: Attention and concentration, memory, speed of processing, executive functioning, Social cognition
    • Mood/anxiety: anxiety, obsessions and compulsions, depression
  6. Define positive symptoms
    • Positive symptoms: comprise excesses and distortions, and include hallucinations and delusions. For the most part, acute episodes of schizophrenia are characterised by positive symptoms.
    • Delusions: beliefs contrary to reality and firmly held in spite of disconfirming evidence.
    • Persecutory delusions: he or she is being tormented, followed, tricked, spied on, or ridiculed. Most common delusion.
    • Thought insertion: A person may believe that thoughts that are not his or her own have been placed in his or her mind by an external source.
    • Thought withdrawal: or have been taken from their minds.
    • Thought alienation: thought insertion and thought withdrawal.
    • Thought broadcasting: A person may believe that his or her thoughts are broadcast or transmitted, so that others know what he or she is thinking. This is sometimes explained as telepathy or ESP.
    • A person may believe that an external force controls his or her feelings or behaviours. For example, a person may believe that his or her behaviour is being controlled by the signals emitted from mobile telephone towers.
    • Grandiose delusions: an exaggerated sense of his or her own importance, power, knowledge or identity.
    • Ideas of reference:  incorporating unimportant events within a delusional framework and reading personal significance into the trivial activities of others. 
    • Misidentification delusions: A person may believe that the people around them have been replaced by imposters, that their parents are not their parents, and the doctors and nurses that they might be treated by are not real health professionals. A variant of this is that someone, usually persecuting the individual, is changing their appearance.

    Although delusions are found among more than half of people with schizophrenia, they are also found among people with other diagnoses, including bipolar disorder, major depressive disorder with psychotic features and delusional disorder.
  7. Positive- Hallucinations and other disturbances of perception
    • Hallucinations: sensory experiences in the absence of any relevant stimulation from the environment.
    • They are more often auditory than visual;
    • 74 ­percent of one sample of people with schizophrenia reported having auditory hallucinations.
    • However, hallucinations can occur in any of the five sensory modalities.
    • Some people with schizophrenia report hearing their own thoughts spoken by another voice. Other people may claim that they hear voices arguing, and others hear voices commenting on their behaviour. 
    • Hallucinations that were believed to come from a known person were experienced more positively.
    • Some theorists propose that people who have auditory hallucinations misattribute their own voice as being someone else’s voice. Behavioural studies have shown that people with hallucinations are more likely to misattribute recordings of their own speech to a different source.

    • Studies have found greater activity in Broca’s area, an area of the frontal cortex that supports our ability to produce speech, and in Wernicke’s area, an area of the ­temporal cortex that supports our ability to understand speech, when people with schizophrenia report hearing voices.
    • One suggestion that unifies these findings is the possibility that people who experience auditory hallucinations fail to accurately predict what sensations should arise from their own actions in a failure of the corollary discharge mechanisms in the brain — the mechanism that unconsciously monitors and matches the results of self-generated actions.

    Not specific to schizophrenia nor are they essential for the diagnosis.

    • Loss of insight: This can manifest as complete and terrified belief in the veracity of symptoms such as hallucinations and delusions, or a bland disagreement about the ­poverty-stricken and disorganised state that the person with schizophrenia might be living in.
    • Poor insight interferes with treatment and is correlated with the severity of the illness.
  8. Brain on fire
    • Lady presented symptoms of schizophrenia but did not respond to anti psychotic medication.
    • Turns out she had autoimmune disease which was attacking specific neurons with NMDA receptors.

    • New treatments for schizophrenia are targeting NMDA receptors (if these receptors are blocked too much, psychotic symptoms can occur). 
    • Some people early in the course of schizophrenia have the NMDA antibodies but not anti-NMDA-receptor-autoimmune encephalitis.
    • Since we do not yet have a blood or brain test for schizophrenia, the diagnosis is made based on the set of observed behavioural symptoms.
    • Thus, mental health professionals would do well not to be too quick to make a diagnosis of schizophrenia or bipolar disorder or any psychological disorder, and instead consider that other factors might be contributing to the symptoms.
  9. Negative symptoms
    • Negative symptoms: consist of behavioural deficits in motivation, pleasure, social closeness and emotion expression.
    • These symptoms tend to endure beyond an acute episode and have profound effects on their lives.
    • They are also important prognostically; the presence of many negative symptoms is a strong predictor of a poor recovery (e.g., occupational impairment, few friends) two years following hospitalisation.
    • They are considered by many as the core features of the disorder.

    • Avolition: or apathy refers to a lack of motivation and a seeming absence of interest in or an inability to persist in what are usually routine activities, including work or school, hobbies or social activities.
    • The researchers found that people with schizophrenia were less motivated by goals about autonomy (self-expression), gaining new knowledge or skills, or praise by others compared to people without schizophrenia but were more motivated by goals that had to do with reducing boredom.
    • However, people with schizophrenia were equally motivated by goals that had to do with relatedness to others and with avoiding a negative outcome (e.g., criticism).
    • Thus, it appears that people with schizophrenia may have trouble with motivation for certain life areas, but not for others.

    Asociality: severe impairments in social relationships. They may have few friends, poor social skills and very little interest in being with other people. They may not desire close relationships with family, friends or romantic partners. Instead, they may wish to spend much of their time alone. When around others, people with this symptom may interact only superficially and briefly, and may appear aloof or indifferent to the social interaction.

    • Anhedonia: A loss of interest in or a reported lessening of the experience of pleasure. 
    • There are two types of pleasure experiences in the anhedonia construct.
    • Consummatory pleasure: refers to the amount of pleasure experienced in the moment or in the presence of something ­pleasurable. 
    • Anticipatory pleasure: refers to the amount of expected or anticipated pleasure from future events or activities. 
    • People with schizophrenia appear to have a deficit in anticipatory pleasure but not consummatory pleasure.

    • Blunted affect: refers to a lack of outward expression of emotion. A person with this symptom may stare vacantly, the muscles of the face motionless, the eyes lifeless. When spoken to, the person may answer in a flat and toneless voice and not look at his or her conversational partner. Blunted affect was found in 66 percent of a large sample of people with schizophrenia.
    • The concept of blunted affect refers only to the outward expression of emotion, not to the patient’s inner experience. 
    • People with schizophrenia are much less facially expressive than are people without schizophrenia however, report experiencing the same amount or even more emotion than people without schizophrenia.

    Alogia: refers to a significant reduction in the amount of speech. Simply put, people with this symptom do not talk much. 

    • Although we have just described five different negative symptoms, research suggests that these symptoms can be understood more simply as representing two domains:
    • Motivation and pleasure domain: involving motivation, ­emotional experience and sociality.
    • Expression domain: involving outward expression of emotion and vocalisation.
  10. Disorganised symptoms
    Disorganised symptoms: include disorganised speech and disorganised behaviour.

    • Disorganised speech: Also known as formal thought disorder. Refers to problems in organising ideas and in speaking so that a listener can understand.
    • Although may make repeated references to central ideas or themes, the images and fragments of thought are not connected; it is difficult to understand what he is trying to tell the interviewer.
    • Speech may also be disorganised by what are called loose associations, in which ideas sound disjointed — they slip into each other, though are still related, and the person appears to have difficulty sticking to one topic.
    • Derailment: As the logical order of thought is further degraded, thoughts are juxtaposed without a meaningful relationship. 
    • eg. ‘cause I pretended like I didn’t know what was going on, I slipped on the floor of the kitchen'
    • Incoherence: As the degree of thought disorder worsens, the person’s speech becomes unintelligible as grammar and content are broken down into smaller sections of seemingly unrelated words.
    • eg. "The time that Jesus Christ people believe in their thing people believed in, Jehovah God that they didn’t believe in Jesus Christ that much. "
    • Word salad: At its worst, disorganised speech is described as word salad. Speech resembles a Dada poem, with words or even syllables chopped up and interspersed in a totally unintelligible way. 

    Disorganised speech is associated with problems in what is called executive functioning — problem solving, planning and making associations between thinking and feeling. Disorganised speech is also related to the ability to perceive semantic information (i.e., the meaning of words)

    • Disorganised behaviour: may go into inexplicable bouts of agitation, dress in unusual clothes, act in a silly manner, hoard food or collect garbage. They seem to lose the ability to organise their behaviour and make it conform to community standards. They also have difficulty performing the tasks of everyday living.
    • Catatonia: one manifestation of disorganised behaviour. People with this symptom may gesture repeatedly, using peculiar and sometimes complex sequences of finger, hand and arm movements, which often seem to be purposeful.
    • Some people manifest an unusual increase in their overall level of activity, including much excitement, flailing of the limbs and great expenditure of energy similar to that seen in mania or be immobile.
    • Immobility: people adopt unusual postures and maintain them for very long periods of time.
    • Catatonia can also involve waxy flexibility — another person can move the person’s limbs into positions that the person will then maintain for long periods of time.
    • Catatonia is seldom seen today in people with schizophrenia in developed countries, perhaps because medications work effectively on these disturbed movements or postures.
    • While once a subtype of schizophrenia, catatonia is now thought of as a neuropsychiatric syndrome that can be seen in mood disorders, neurological diseases, drug intoxication and developmental disorders as well as in schizophrenia.
  11. Cognition
    • Cognitive deficits in schizophrenia are common and include both neurocognition (attention, ­concentration, memory, speed of processing and executive functioning) and social cognition (emotion recognition, theory of mind, attributional bias).
    • Although these difficulties are not as easily assessed as hallucinations and delusions, they are even more significant than the positive symptoms in determining functional ­outcome.
    • These deficits are demonstrable prior to the onset of ­schizophrenia worsen at the time of first presentation of schizophrenia and then appear to stabilise.
    • These deficits appear to be broad rather than selective and vary in degree from mild to very severe. This leaves individuals with ­schizophrenia still capable of working, studying and playing their part in our communities; however, it does limit their potential.

    • Problems with attention and concentration make it difficult to register new information and to follow events. 
    • Memory deficits make it harder to retain information in the workplace or at school. The decreased speed of processing may make it harder to keep up with others at work.
    • Social cognitive deficits are a major barrier for many undermining the ability of individuals with schizophrenia to recognise the emotional state of people, leaving them alienated from the interaction between colleagues and prone to distortions in their explanatory model for what is happening around them.
  12. Anxiety and depression
    • Anxiety and depression are very common in people with schizophrenia, both as part of the syndrome of the disorder and as a comorbid condition such as panic disorder or major depressive disorder.
    • These symptoms significantly contribute to the level of disability and mortality.
    • Anxiety and depressive symptoms are commonly observed as part of the prodrome of schizophrenia — the period during the development of the disorder when the individual may not demonstrate all of the features needed for diagnosis. 
    • Prospectively, this has become known as the at-risk mental state.
    • During the period of recovery from the initial acute stages of schizophrenia, the interplay between symptoms can be ambiguous; for example, differentiating between residual persecutory fears and social avoidance as part of social anxiety can be difficult.
  13. History of the concept of schizophrenia
    • Needed to specify some common denominator or essential property that would link the various disturbances. The metaphorical concept that he adopted for this purpose was the ‘breaking of associative threads’.
    • For Bleuler, associative threads joined not only words but also thoughts. Thus, goal-directed, efficient thinking and communication were possible only when these hypothetical structures were intact. 
    • The notion that associative threads were disrupted in people with ­schizophrenia could then be used to account for the range of other disturbances. Bleuler viewed attentional difficulties, for example, as resulting from a loss of purposeful direction in thought, in turn causing passive responses to objects and people in the immediate surroundings.
  14. Schizophrenia and the DSM-5
    • Symptoms last at least six months for the diagnosis of schizophrenia to be made.
    • The six-month period must include at least one month of an acute episode or active phase, defined by the presence of at least two of the following symptoms: delusions, hallucinations, disorganised speech, ­disorganised behaviour and negative symptoms, one of which has to be delusions, hallucinations or disorganisation.
    • The remaining time required for the diagnosis can occur either before or after the active phase.
    • This time criterion eliminates people who have a brief psychotic episode and then recover quickly.

    The traditional subtypes of schizophrenia (i.e., paranoid, disorganised, catatonic, undifferentiated) are no longer used in the classification as they were of questionable usefulness, poor reliability and poor predictive validity.

    • Two other psychotic disorders that should be considered are
    • schizophreniform disorder: symptoms are the same as those of schizophrenia but last only one to six months.
    • Brief psychotic disorder:  lasts from one day to one month and can be brought on by extreme stress.
    • DSM-5 made only one change regarding these two disorders: the symptoms must include hallucinations, delusions or disorganised speech.
    • Schizoaffective disorder: comprises a mixture of symptoms of schizophrenia and mood disorders.

    Delusional disorder: troubled by persistent delusions. 

    • Other conditions that can present in a similar fashion to schizophrenia include the manic phase of a bipolar disorder when people can appear elevated in mood, highly disorganised and psychotic.
    • Psychotic symptoms can also occur in the context of substance abuse (intoxication or withdrawal) of many ­psychoactive substances.
  15. Attenuated psychosis syndrome (APS)
    • Detecting youth who are high risk of psychosis.
    • The idea for attenuated psychosis syndrome (APS) came from research over the past two decades that has sought to identify young people who are at risk for developing schizophrenia.
    • Prospective longitudinal study.
    • Identify youth at elevated risk of developing psychosis through genetic risk or present mild symptoms that might develop later.
    • Risk increased with time, with 22 percent transitioning to psychosis after one year and 36 percent transitioning after three years compared to 0.2% of population.

    • A longer duration of undiagnosed psychosis (DUP) is associated with a higher symptom load, poorer overall functioning and a reduced likelihood of gaining remission.
    • Also, even if the person with APS did not go on to develop schizophrenia, they were at high risk of developing a persistent non-psychotic mental disorder so identifying people with APS and bringing them to care is important.

    • Arguments against recognising APS as a new diagnostic category:
    • First, the category itself does not yet have enough reliability and validity to support its use as a formal diagnosis.
    •  Second, there is a high level of comorbidity with prodromal (early) symptoms: over 60 percent of young people meeting the prodromal criteria have a history of depression, raising questions as to where in the present classification APS should be: is it part of a mood disorder or a schizophrenia spectrum disorder?
    • Third, there is concern that applying a new diagnostic label, particularly to young people, might be stigmatising or lead to discrimination. Because not all people with APS will develop schizophrenia, it may unnecessarily alarm young people and their families.
    •  Finally, while providing treatment for people with distressing or disabling attenuated positive symptoms is a laudable goal, there is concern that the treatment will too closely resemble that for schizophrenia, further blurring the line between the two conditions.
  16. Aetiology- genetic
    Behavioural studies
    • Current evidence indicates that schizophrenia is genetically heterogeneous — that is, genetic factors may vary from case to case — mirroring the fact, noted earlier, that schizophrenia is symptomatically heterogeneous.
    • Behaviour genetics research: Family, twin and adoption studies support the idea that genetic factors play a role in schizophrenia.
    • Family studies: risk follows a gradient from the person with whom an individual with schizophrenia (the proband) would share all of their genetic material.
    • Findings suggests that negative symptoms may have a stronger genetic component.
    • An important issue is that schizophrenia shares its inheritance with a range of other mental disorders
    • Findings suggest that there may be some shared genetic vulnerability between schizophrenia and other severe mental illnesses like bipolar disorder.
    • It has been estimated that while the genetic liability for schizophrenia accounted for 81 percent of the risk, there is an effect for the shared environment of 11 percent for twins.

    • Twin studies: The risk for MZ twins (44.3 percent), though greater than that for DZ twins (12.08 percent), is still much less than 100 percent.
    • Indeed, the rate of schizophrenia and schizophrenia-like psychoses in the children of the MZ twins without schizophrenia was 9.4 percent, while the rate among the children of the twins with schizophrenia was only slightly and non-significantly higher, 12.3 percent, which lends further support to the importance of genetic factors in schizophrenia.

    • Adoption studies: Such studies eliminate the possible effects of being reared in an environment where a parent has schizophrenia.
    • A fivefold increase in the odds ratio for developing schizophrenia is seen in the offspring of mothers with schizophrenia who place their child for adoption compared to a control population.
  17. Aetiology- genetic
    Molecular genetics research
    • Understanding exactly what constitutes the genetic predisposition is the challenge faced by molecular genetics researchers.
    • Not transmitted by a single gene.
    • Multiple common genes associated with schizophrenia, bipolar ­disorder, major depression and autistic spectrum disorder, the strongest being the link between schizophrenia and bipolar disorder.

    • The genetic risks for schizophrenia can be understood as deriving from one of three general classes:
    • (1) copy number variations (CNV) that have arisen de novo- refers to an abnormal copy (a deletion or a duplication) of one or more sections of DNA in a gene.
    • This rare though potent cause of disease is found at an increased rate in schizophrenia (approximately 5 percent) as compared to ­controls (2 percent) as well as in a range of other neurodevelopmental disorders such as autism and mental retardation.
    • (2) rare alleles or CNV of high risk and
    • (3) common polymorphisms of low risk.
    • This rare though potent cause of disease is found at an increased rate in schizophrenia (approximately 5 percent) as compared to ­controls (2 percent) as well as in a range of other neurodevelopmental disorders such as autism and mental retardation.
    • In the case of individuals who go on to develop schizophrenia, these new genetic materials frequently are associated with the glutamatergic synapse involving both activity-regulated cytoskeleton-associated protein (ARC) and N-methyl-D-aspartate receptor (NMDAR) complexes, as well as proteins that regulate synaptic strength. 
    • A small number of rare inherited CNV abnormalities have also been associated with schizophrenia. 

    • Study emphasised the polygenetic nature of schizophrenia, giving support to the conception of schizophrenia as a syndrome with multiple overlapping possible aetiologies.
    • Genes associated with the dopamine D2 receptor (DRD2), glutamatergic transmission (GRM3, GRIN2A, SRR, GRIA1), calcium channel proteins and synaptic proteins were consistent with prior findings, and with proposed mechanisms of aetiology or treatment.
    • In addition, the study pointed to a possible strong role for immune dysfunction in schizophrenia.
    • In fact, the strongest association identified was with the genes that coded for the major histocompatibility complex.
    • This insight has already provided researchers with a mechanism for the dysfunction in synaptic pruning that is known to occur in ­schizophrenia.
    • A specific variant of the complement C4 gene was found to be increased in people with schizophrenia and expressed at a higher rate in the brains of people with schizophrenia. This variant was associated with an increase in the elimination of synapses due to an interaction with microglia in the brain. This has been heralded as the first convincing physiological explanation for brain changes in schizophrenia.
  18. The role of neurotransmitters- dopamine
    • Dopamine theory: 
    • Original domaine hypothesis of schizophrenia: The original dopamine hypothesis proposed that a global hyperactivity of the dopaminergic projections in the brain may lead to the symptoms of schizophrenia.
    • Revised dopamine hypothesis: proposed that a hyperactive nigrostriatal dopaminergic projection leads to positive symptoms but a hypoactive mesocortical projection is responsible for cognitive and negative symptoms.

    • The theory that schizophrenia is related to excess activity of the neurotransmitter dopamine is based principally on the knowledge that drugs effective in treating schizophrenia reduce dopamine activity. 
    • Researchers have noted that antipsychotic drugs, in addition to being useful in treating some symptoms of schizophrenia, produce adverse effects resembling the symptoms of Parkinson’s disease.
    • Parkinson’s disease is caused in part by low levels of dopamine in a particular area of the brain. 
    • Antipsychotic drugs fit into and thereby block a particular type of postsynaptic dopamine receptor, called D2 receptors. 
    • Further indirect support for the dopamine theory came from findings that antipsychotics were able to block the psychomotor activity associated with stimulant medications such as amphetamines and stimulant medications could produce a state that closely resembles schizophrenia in people who do not have the disorder; they can also exacerbate the symptoms of people with schizophrenia.

    • Concluded that excess striatal dopamine drives the positive and disorganisation symptoms of schizophrenia and that this excess is most probably presynaptic.
    • It is not accompanied by significant changes in post-synaptic D2 receptors or changes in dopamine transporter function.
    • Antipsychotic medications suppress these symptoms by blocking dopamine D2 receptors in the mesolimbic pathway, thereby lowering dopamine activity; however, they do not alter the underlying pathology that is driving the symptomatology.
    •  Hence any non-adherence or hasty reduction in medication dose may result in a rapid return of symptoms. 
    • These changes in the striatum are accompanied by a decreased dopamine release in the prefrontal cortex, which has been related to both the negative and cognitive symptoms of schizophrenia.

    Because schizophrenia is a disorder with widespread symptoms related to perception, emotion, cognition and social behaviour, it is unlikely that a single neurotransmitter could account for all symptoms. Thus, schizophrenia researchers have cast a broader neurotransmitter net, moving away from an emphasis on dopamine.
  19. Other neurotransmitters
    • As we discuss later, newer drugs used in treating schizophrenia implicate other neurotransmitters, such as serotonin.
    • These newer drugs partially block D2 receptors, but they also work by blocking the serotonin receptor 5-HT2A.
    • Dopamine neurons generally ­modulate the activity of other neural systems; for example, in the prefrontal cortex they regulate gamma-aminobutyric acid (GABA) neurons. Thus, it is not surprising that GABA transmission is disrupted in the prefrontal cortex of people with schizophrenia.
    • Similarly, serotonin neurons regulate dopamine neurons in the mesolimbic pathway.

    • Glutamate, a neurotransmitter that is widespread in the human brain, may also play a role. 
    • Low levels of glutamate have been found in the cerebrospinal fluid of people with schizophrenia and postmortem studies have revealed low levels of the enzyme needed to produce glutamate.

    • Studies have found elevated levels of the amino acid homocysteine, a substance that is known to interact with the NMDA receptor among people with schizophrenia and, during their third trimester, in the blood of pregnant women whose offspring developed schizophrenia as adults.
    • The anaesthetic phencyclidine (PCP) can induce both positive and negative symptoms in people without schizophrenia by antagonising glutamate at NMDA receptors.
    • Furthermore, a decrease in glutamate inputs from either the prefrontal cortex or the hippocampus (both of these brain structures are implicated in schizophrenia) to the corpus striatum could result in increased dopamine activity.
    • Additional evidence suggests that cognitive deficits in schizophrenia supported by the prefrontal cortex as well as symptoms of disorganisation may be connected to deficits involving NMDA.
  20. Integrating neurotransmitter and genetic factors leading to psychosis
    Put picture in

    • Genetic work points to the involvement of dopaminergic, glutamatergic and GABAergic systems.
    • These changes clearly increase the vulnerability of the brain to aberrant neurodevelopment and the effects of stress. 
    • We suspect that this system is primed for the development of schizophrenia by dysfunction in glutamatergic (excitatory) control, leading to a loss of regulatory feedback in the striatum contributing to the increase in striatal dopamine.
    • It is this spiking of dopaminergic activity that is associated with disorganisation and positive symptoms.
    • The decrease in glutamatergic activity and associated dopaminergic activity in the prefrontal cortex (PFC) is accompanied by the negative and cognitive symptoms of schizophrenia.
  21. Brain structure and function
    • Enlarged ventricles: The brain has four ventricles, which are spaces in the brain filled with cerebrospinal fluid. Having larger fluid-filled spaces in and around the brain implies a loss of brain cells. Not because of medication.
    • Large ventricles in people with schizophrenia are correlated with impaired performance on neuropsychological tests, poor functioning prior to the onset of the disorder and poor response to medication treatment.
    • The extent to which the ventricles are enlarged, however, is modest. 
    • Furthermore, enlarged ventricles are not specific to schizophrenia.

    • Prefrontal cortex: A variety of evidence suggests that the prefrontal cortex is of particular importance in schizophrenia. The prefrontal cortex is known to play a role in behaviours such as speech, decision making, emotion and goal-directed behaviour, which are disrupted in schizophrenia.
    • Reductions in grey matter and overall volume in the prefrontal cortex. These changes are associated with the transition to psychosis in people with an at-risk mental state or APS. 
    • The duration of relapse of psychosis is negatively correlated with frontal lobe and total brain volume.
    • People with schizophrenia perform more poorly than people without schizophrenia on neuropsychological tests designed to tap functions supported by the prefrontal region, including working memory or the ability to hold bits of information in memory.
    • People with schizophrenia show lower glucose ­metabolism in the prefrontal cortex when performing neuropsychological tests tapping prefrontal function.
    • Finally, failure to show frontal activation is related to the severity of negative symptoms.

    • Despite the reduced volume of the grey matter in the prefrontal cortex (and also the temporal cortex), the number of neurons in this area does not appear to be reduced. More detailed studies indicate that what is lost may be what are called ‘dendritic spines’ .
    • Dendritic spines are small ­projections on the shafts of dendrites where nerve impulses are received from other neurons at the synapse.
    • The loss of these dendritic spines means that communication among neurons (i.e., functioning of the synapses) is disrupted, resulting in what some have termed a ‘disconnection syndrome’.
    • One possible result of the failure of neural systems to communicate could be the speech and behavioural disorganisation seen in schizophrenia.

    Genetic variation in the C4 component of this cascade has been associated with the accelerated destruction of synapses in the brain possibly by prompting microglia to aggressively phagocytose these synapses
  22. Problems in the temporal cortex and surrounding regions
    • people with schizophrenia have structural and functional abnormalities in the temporal cortex, including areas such as the temporal gyrus, hippocampus, amygdala and anterior cingulate. 
    • A twin study found reduced hippocampus volume among twins with ­schizophrenia, but not among the twins without schizophrenia.
    • Relatives of people with schizophrenia had smaller hippocampal volumes than relatives of people without schizophrenia. These findings suggest that reduced hippocampal volume in people with schizophrenia may reflect a combination of genetic and environmental factors.

    • What makes these findings about the hippocampus all the more intriguing is the fact that the hypothalamic–pituitary–adrenal (HPA) axis is closely connected to this area of the brain. 
    • Chronic stress is associated with reductions in hippocampal volume in other disorders.
    • Although people with schizophrenia do not necessarily experience more stress than people without schizophrenia, they are more reactive to stress.
    • Taken together, stress reactivity and a disrupted HPA axis likely contribute to the reductions in hippocampal volume observed in people with ­schizophrenia
  23. Connectivity in the brain
    • It is possible that schizophrenia occurs as the result of long-term neurodevelopmental changes in the ‘connectome’ of the brain.
    • Broadly speaking, there are three types of connectivity.
    • 1. structural (or anatomical) connectivity refers to how different structures of the brain are connected via white matter (axon fibres).
    • Studies have found that people with schizophrenia have less connectivity in brain white matter than people without schizophrenia in the frontal and temporal cortices.
    • 2. Functional connectivity refers to the connectivity between brain regions based on correlations between their blood oxygen level dependent (BOLD) signal measured with fMRI.
    • Several studies have found reduced functional connectivity in schizophrenia, particularly in the frontal cortex.
    • Effective connectivity: combines both types of connectivity in that it not only reveals correlations between BOLD activations in different brain regions but also the direction and timing of those activations by showing, for example, that activation in the occipital cortex comes first, followed by ­activation on the frontal cortex when someone is viewing pictures of objects. Like the other types of connectivity, research has found diminished effective connectivity in schizophrenia.

    • These connectivity methods have revealed a number of what are called brain networks. Networks are clusters of brain regions that are connected to one another in that activation in these regions is reliably correlated when people perform certain types of tasks or are at rest.
    • Other brain connectivity research in schizophrenia has revealed that there is less connectivity between brain networks, including the frontoparietal and default-mode networks and this diminished connectivity is correlated with poor performance on cognitive tests.
    • Research has also found diminished connectivity among healthy relatives of people with schizophrenia, suggesting that diminished connectivity might be part of the genetic diathesis for schizophrenia.
  24. 6.4 Environmental factors influencing the developing brain
    • Damage during gestation or birth: Many studies have shown high rates of delivery complications in people with schizophrenia. Such complications could have resulted in a reduced supply of oxygen to the brain, resulting in loss of cortical grey matter.
    • Rather, the risk for schizophrenia is increased in those who experience complications and have a genetic diathesis.

    Starvation: associated with an increased risk of schizophrenia. Cohort dutch after WW2. The effect upon foetuses during the first trimester of development was marked with a doubling of the risk of developing schizophrenia. Happened in China famine also.

    Maternal infections during pregnancy: associated with greater risk of their children developing schizophrenia when they become adults. 

    Prenatal Influenza: infection. people who had been exposed to the flu virus during the second trimester of pregnancy had much higher rates of schizophrenia than those who had been exposed in either of the other trimesters and much higher rates than non-exposed control adults.
  25. If the damage to brain happens early, why does the disorder begin many years later?
    • The prefrontal cortex is a brain structure that matures late, typically in adolescence or early adulthood. Thus, a problem in this area, even one that begins early in the course of development, may not show itself in the person’s behaviour until the period of development when the ­prefrontal cortex begins to play a larger role in behaviour.
    • Notably, dopamine activity also peaks in adolescence, which may further set the stage for the onset of schizophrenia symptoms.
    • Adolescence is also typically a developmental period that is fraught with stress.
    • Stress activates the HPA axis, causing cortisol to be secreted. Cortisol increases dopamine activity, particularly in the mesolimbic pathway, perhaps increasing the likelihood of developing schizophrenia symptoms.

    Another proposed explanation:  the development of symptoms in adolescence could reflect a loss of synapses due to excessive pruning, the elimination of synaptic connections.

    • Cannabis use: Among people already diagnosed with schizophrenia, cannabis use is associated with a higher level of positive symptoms, depression and poorer functioning, particularly in people early in the course of their illness.
    • The risk of developing schizophrenia symptoms was greater among those who used cannabis.
    • Study showed cannabis users had an earlier age of onset for psychosis.
    • Furthermore, more frequent use and higher potency cannabis are associated with greater risk.
    • However, correlation does not mean causation. Other studies suggest that the linkage between cannabis use and risk of developing schizophrenia is observed only among those who are genetically vulnerable to schizophrenia.

    An increased risk of psychosis has been associated with a particular polymorphism in the COMT gene (Caspi et al., 2005) and the AKT1 gene (Di Forti et al., 2012). Both vulnerabilities required the abuse of cannabis to activate the risk associated with them.
  26. Psychological factors
    Stress: People with schizophrenia do not appear to experience more stress in daily life than people without schizophrenia but are more reactive.

    • Socioeconomic status: highest rates of schizophrenia are found in people with the lowest SES.
    • The correlation between SES and schizophrenia is consistent but difficult to interpret in causal terms. 
    • Sociogenic hypothesis: Is it that the stress associated with poverty, such as low education, limited opportunities and stigma from others of high status contributes to the development of schizophrenia?
    • Social selection hypothesis: Or is it the case that during the course of their developing illness, people with schizophrenia drift into poor neighbourhoods because their illness impairs their earning power and they cannot afford to live elsewhere?
    • Jew immigration study are more supportive of the social selection hypothesis than of the sociogenic hypothesis.

    • Family-related factors: the findings are only suggestive, not conclusive. For example, a few studies of families of people with schizophrenia have found that they communicate more vaguely with one another and have higher levels of conflict than families of people without schizophrenia. It is plausible, though, that the conflict and unclear communication are a response to having a young family member with schizophrenia.
    • Families and relapse: only 10 percent of the people returning to low-EE homes had relapsed, but 58 percent of the people returning to high-EE homes had gone back to the hospital.
    • EE expressed emotion: critical comments, hostility and emotional overinvolvement.
    •  the relationship between emotional ­overinvolvement and relapse in other European and Asian countries is not as robust as it is in North American countries.
    • The different findings may be attributed either to the fact that emotional overinvolvement is measured differently across countries and cultures or that emotional overinvolvement is more harmful in some cultures and countries than in others.
    • What is not yet clear is exactly how to interpret the effects of EE. Is EE causal or does it reflect a reaction to the ill relative’s behaviour?

    • Thus, this study found a bidirectional relationship in high-EE families: critical comments by family members elicited more unusual thoughts by relatives with schizophrenia and unusual thoughts expressed by the relatives with schizophrenia led to increased critical comments.
    • Through stress, HPA, cortisol, dopamine
  27. Developmental factors
    • Retrospective studies: the children who later developed schizophrenia as young adults showed poorer motor skills and more expressions of negative emotions.
    • Adults with schizophrenia scored lower on IQ and other cognitive tests as children compared to adults without schizophrenia 

    • Prospective studies: found that lower scores on the IQ test in childhood predicted the onset of schizophrenia in young adulthood, even after they controlled for low socioeconomic status (which is associated with lower IQ scores).
    • he group with schizophrenia also suffered a significant decline from 13 to 32 years of age across a range of cognitive tasks including full-scale IQ, speed of processing, executive skills, learning and motor function.
    • These findings are broadly consistent with the idea that something goes awry in development that is associated with the onset of schizophrenia in late adolescence or early adulthood. 

    • Familial high-risk study: follows offspring of 1 or 2 parents with schizophrenia. 
    • One of the difficulties with familial high-risk studies has to do with the large sample sizes that are required.
    • Around 10 percent of children with a biological parent who has schizophrenia go on to develop schizophrenia. 

    Clinical high-risk study: A clinical high-risk study is a design that identifies people with early, attenuated signs of schizophrenia, most often milder forms of hallucinations, delusions or disorganisation that nonetheless cause impairment.
  28. Treatment of schizophrenia
    • Treatments for schizophrenia most often include a combination of short-term hospital stays (during the acute phases of the illness), medication and psychosocial treatment. 
    • A problem with treatment is that some people with schizophrenia lack insight into their impaired condition and may refuse treatment.
    • Study suggest that gender (female) and age (older) are predictors of better insight among people in their first episode of the illness and this may help account for why women with schizophrenia tend to respond better to treatment than men.

    • Medications
    • Antipsychotic drugs: aka neuleptics or major tranquillisers. Found to help with the positive symptoms and disorganisation of schizophrenia.
    • eg. chlorpromazine:  proved very effective in calming people with schizophrenia. Phenothiazines derive their antipsychotic properties from blocking dopamine receptors in the brain, thus reducing the influence of dopamine on thought, emotion and behaviour. 
    • Adverse reactions: involuntary movements of the face, arms and legs (dopaminergic), sedation (histaminic), weight gain (range of receptor and hormonal effects) and dry mouth or blurry vision (anticholinergic).
    • Did not treat all of the symptoms of schizophrenia and that, in particular, the negative and cognitive symptoms were at best only partially treated.
    • Introduction of the second-generation antipsychotics that were thought to have broader neurotransmitter effects, such as effects upon the serotonin 5-HT2A receptor.
  29. First generation antipsychotic drugs and their adverse effects
    • The first-generation antipsychotic drugs are those broad classes of medications that were the first to be discovered. 
    • These drugs can reduce the positive and disorganisation symptoms of schizophrenia but have little or no effect on the negative and cognitive symptoms, perhaps because their primary mechanism of action involves blocking dopamine D2 receptors.
    • Not a cure.
    • People who respond positively to the antipsychotics are typically kept on so-called maintenance doses of the drug to continue the therapeutic effect.
    • trials comparing either first- or second-generation drugs to placebo found that maintenance dosages of both were equally effective at reducing relapse compared to placebo.
    • Some symptoms may be controlled, but lives are still not fulfilling for many people with schizophrenia.

    • Adverse effects:
    • The commonly reported adverse effects of all antipsychotics include sedation, dizziness, blurred vision, restlessness and sexual dysfunction.
    • extrapyramidal adverse effects: resemble the symptoms of Parkinson’s disease. Tremors of the hands and fingers, a shuffling gait, a blank mask-like face and drooling.
    • Other adverse effects can include dystonia, a state of muscular rigidity or spasm, and dyskinesia, an abnormal motion of voluntary and involuntary muscles, producing chewing movements of the tongue and jaw as well as other movements of the lips, fingers and legs. Another adverse effect is akathisia, an inability to remain still; people who have this adverse effect pace constantly and fidget.
    • Tardive dyskinesia: the mouth muscles involuntarily make sucking, lip-smacking and chin-wagging motions. In more severe cases, the whole body can be ­subject to involuntary motor movements. This syndrome is observed mainly in older people with schizophrenia who had been treated with first-generation medications before drugs were developed to prevent ­tardive dyskinesia.  It affects about 10 to 20 percent of these older people treated with first-generation antipsychotics for a long period of time and is not responsive to any known treatment.
    • Neuroleptic malignant syndrome: occurs in about 1 percent of cases. In this condition, which can sometimes be fatal, severe muscular rigidity develops, accompanied by fever. The heart races, blood pressure is unstable and the person may lapse into a coma.

    Because of these serious adverse effects, current Australian clinical practice guidelines advise that the lowest effective dose of medication be given and that close attention be given to the balance of beneficial effect as against adverse effect for the individual.
  30. Second-generation antipsychotic drugs and their adverse effects
    • second-generation antipsychotic drugs: because their mechanism of action is not like that of the typical or first-generation antipsychotic medications.
    • However, they do not form a single pharmacological class and really could be called ‘new’ as against ‘old’ antipsychotic medications.
    • Clozapine remains the most effective of the antipsychotic medications.
    • Adverse effects: weight gain,  increased secretion of prolactin, a heart rhythm change, sedation.
    • 2nd gen preferred and lower relapse.
    • Given adverse effects, alternate dosing strategies such as drug holidays and early cessation of use have been studied. 
    • Found a higher rate of recovery in those allocated to the treatment discontinuation arm of the trial, even though they had a higher rate of relapse initially
  31. Evaluation of drug treatments
    • Antipsychotic drugs are an indispensable part of treatment for schizophrenia.
    • Furthermore, the mixed success of second-generation antipsychotic drugs has stimulated a continued effort to find new and more effective drug therapies for schizophrenia.
  32. Psychological treatments
    Social skills training
    family therapy
    A number of psychosocial interventions, including skills training, cognitive–behavioural therapy, cognitive remediation therapy and family-based treatments, have a solid evidence base to support their use as an adjunctive treatment to medications.

    • Social skills training: designed to teach people with schizophrenia how to successfully manage a wide variety of interpersonal situations. 
    • Research has shown that social skills training can help people with schizophrenia achieve fewer relapses, better social functioning and a higher quality of life.

    • Family therapies: high levels of expressed emotion (EE) within the family, including being hostile, critical and emotionally overinvolved, have been linked to relapse and rehospitalisation.
    • Education about schizophrenia. Specifically, education about the genetic or neurobiological factors that predispose some people to the illness, the cognitive problems associated with schizophrenia, the symptoms of schizophrenia and the signs of impending relapse.
    • Information about antipsychotic medication. 
    • Blame avoidance and reduction. Therapists encourage family members to blame neither themselves nor their relative for the illness and for the difficulties all are having in coping with it.
    • Communication and problem-solving skills within the family. Therapists focus on teaching the family ways to express both positive and negative feelings in a constructive, empathic, non-demanding manner.
    • Social network expansion.
    • Hope. Therapists instil hope that things can improve.
    • Compared with standard treatments (usually just medication), family therapy plus medication has typically lowered relapse over periods of one to two years.
  33. CBT
    • Now, however, a growing body of evidence demonstrates that the maladaptive beliefs of some people with schizophrenia can in fact benefit from cognitive–behavioural therapy (CBT).
    • People with schizophrenia can be encouraged to test out their delusional beliefs in much the same way as people without schizophrenia do.
    • Researchers have found that CBT can also reduce negative symptoms, for example, by challenging belief structures tied to low expectations for success (avolition) and low expectations for pleasure (anticipatory pleasure deficit in anhedonia).
    • Cognitive–behavioural therapy has also been used in the treatment of people meeting the at-risk mental state criteria.
    • helps break down the isolation of people in this situation and provides them with a cognitive framework with which to cope with their unusual perceptual experiences and ideas. It has reduced the transition rate to psychosis in some.
  34. Cognitive remediation therapies
    • or cognitive enhancement therapy (CET) or cognitive training.
    • Researchers and clinicians have been paying more attention to fundamental aspects of cognition that are disordered in schizophrenia in an attempt to improve these functions and thereby favourably affect behaviour. 
    • Treatments that seek to enhance basic cognitive functions such as verbal learning ability.
    •  CET was associated with improvements in social functioning that remained one year after the treatment ended.
    • CET was more effective than EST in improving cognitive abilities in problem solving, attention, social cognition and social adjustment, while symptom reduction was the same for both treatments.
    • Thus, CET appears to be effective in reducing symptoms and improving cognitive abilities and it is linked to good functional outcomes, such as employment and social functioning.

    • Cognitive remediation therapy aimed specifically at social cognitive deficits has also been developed. This aims to treat the underlying dysfunction in social cognitive domains such as emotion recognition, theory of mind deficits and attributional biases.
    •  A range of treatments has been ­developed to address these deficits including programs that specifically teach individuals where to look to understand facial emotion or help improve a person’s understanding of the implicit social rules of an interaction or what other people might be thinking or feeling.
  35. Psychoeducation
    • As we discussed in the chapter on mood disorders with regard to bipolar disorder, psychoeducation is an approach that seeks to educate people about their illness, including the symptoms of the disorder, the expected time course of symptoms, the biological and psychological triggers for symptoms and treatment strategies. 
    • In combination with medication, it was effective in reducing relapse and rehospitalisation and increasing medication compliance
  36. Case management
    community mental health services were established to help coordinate and provide services to people with a severe mental illness like schizophrenia. These services have been developed in a number of different models.

    The simplest model is that of the case manager as the broker of services. Because case managers were familiar with the system, they were able to connect people with schizophrenia with providers of whatever services they required. 

    Extended Hours Team can be developed that provides case management and emergency care if a person relapses, but in a reactive way.

    • assertive case management. In this model the case managers provided direct clinical services in a multidisciplinary team rather than broker them out. 
    • a multidisciplinary team that provides services in the community, such as medication, treatment for substance abuse, help in dealing with stressors that people with schizophrenia face regularly (such as managing money), psychotherapy, vocational training, and assistance in obtaining housing and employment.

    • This more intensive treatment has proven superior to less intensive methods in reducing time spent in the hospital, improving housing stability and ameliorating symptoms.
    • However, more intensive case management has not shown positive effects in other domains, such as improvement in social functioning.
  37. Supported employment
    • In Australia only 22.4 percent of people with psychosis are in full-time paid employment.
    • Supported employment is a model of intervention that places people with a disability directly in the workplace and then supports them in maintaining that employment.
    • The model is most successful when the employment services are integrated with the mental health services and the supporting employment specialist has full access to the individual in their workplace.
  38. Recovery
    a deeply personal, unique process of changing one’s attitudes, values, feelings, goals, skills and/or roles. It is a way of living a satisfying, hopeful and contributing life even with limitations caused by illness. Recovery involves the development of new meaning and purpose in one’s life as one grows beyond the catastrophic effects of mental illness. 

    As such, recovery has qualities that are outside the usual biomedical model of treatment in that it is an individual process that anticipates growth and development as part of a journey. It places the ­individual at the centre, empowering that person, giving them the right and responsibility to decide upon their own goals and make their own decisions. It sees the journey as one made with others as people become integrated into the community rather than being segregated, stigmatised because of their illness
Card Set
Wk 10: Schizophrenia
Wk 10: Schizophrenia 6.1 describe the clinical symptoms of schizophrenia, including positive, negative and disorganised symptoms 6.2 differentiate the genetic factors, both behavioural and molecular, in the aetiology of schizophrenia 6.3 describe how the brain has been implicated in schizophrenia 6.4 describe the role of environmental factors in the aetiology and relapse of schizophrenia 6.5 discuss the appropriate use of medication and psychological treatments for schizophrenia.